General Methods for α- or β-O-Ser/Thr Glycosides and Glycopeptides. Solid-Phase Synthesis of O-Glycosyl Cyclic Enkephalin Analogues

O-Linked glycopeptides have been efficiently synthesized using the highly nucleophilic α-imino esters (O'Donnell's Schiff bases) derived from l-serine (3a–c), l-threonine (4a,b), and a dipeptide ester (5). General methodology has been developed which can provide β-glycosides of β-hydroxy-α-amino acid derivatives 6-16 in excellent yield (63–94%) and excellent selectivity (>20:1) using Hanessian's modification or Helferich's modification of the Koenigs-Knorr reaction. Likewise, selective α-glycosylation has been achieved using the in situ anomerization methodology of Lemieux (28,30). The increased nucleophilicity of the serine/threonine hydroxyl has been shown to be due to intramolecular hydrogen bonding to the N=CPh₂ moiety. Deprotection of the intermediate Schiff bases has been demonstrated, and the glycosides have been incorporated into fully deprotected O-linked glycopeptides in high yield using either solution-phase peptide methods or solid-phase Fmoc-based technology. The potent glycosylenkephalin analogue 38 has been prepared using the solid-phase methodology.